In recent studies in this laboratory, evidence has been obtained that chlorpropamide, an oral antidiabetic drug, inhibits glucagon-stimulated gluconeogenesis in perfused livers of fasted rats and simultaneously lowers hepatic cyclic AMP levels. Crossover analysis of gluconeogenic intermediates suggests that glucagon stimulates, whereas chlorpropamide blocks, the conversion of pyruvate to oxalacetate. In the concentrations used (10 minus 3M), chlorpropamide does not lower hepatic ATP levels or energy charge. During the next year, we expect to study the effect of selective blockade of the oxidation of long-chain fatty acids on gluconeogenesis in perfused livers of fasted rats, using (plus - octanoylcarnitine or methyl 2-tetradecylglycidate as the blocking agent. In addition, we wish to determine whether insulin can be shown to inhibit gluconeogenesis and - if so - whether this can be ascribed to stimulation of pyruvate oxidation or to diversion of lguconeogenic precursors into glycogen or triglyceride formation. Finally, we want to know whether the antigluconeogenic effects of insulin can be enhanced by selective blockade of fatty acid oxidation.